Pharmaceutical composition for parenteral administration containing an indole-carboxylic acid

ABSTRACT

A pharmaceutical composition is disclosed in a form suitable for parenteral administration, comprising a solution of the glycine antagonist, (E)-3- 2-(phenylcarbamoyl) ethenyl!-4,6-dichloroindole-2-carboxylic acid, or a physiologically acceptable salt thereof, in an isotonic sugar solution containing a water miscible organic solvent for the compound, said formulation having a pH within the range of 7 to 9.

This application is a 371 of PCT/EP96/00515 filed Feb. 8, 1996.

This invention relates to pharmaceutical composition for parenteraladministration. More particularly it relates to aqueous formulations ofa glycine antagonist for parenteral administration.

UK Patent Application GB 2266091A describes (E)32-(phenylcarbamoyl)ethenyl!)-4,6-dichloroindole-2-carboxylic acid andphysiologically acceptable salts or metabolically labile esters thereofwhich exhibit antagonist activity at the strychnine insensitive glycinebinding site associated with the NMDA receptor complex. Further thespecification teaches that the compound may be formulated for parenteraladministration and in particular an aqueous solution for injectionconsisting of the active ingredient, sodium phosphate, water forinjection and sufficient sodium hydroxide to adjust to the pH or thesolution to within the range 3-10.

We have now surprisingly found that an improved formulation forparenteral administration may be obtained if the glycine antagonist isformulated in an isotonic sugar solution suitable for injectioncontaining a water miscible organic solvent for the compound and the pHof the solution is adjusted to be within the range 7 to 9.

Thus the present invention provides a pharmaceutical composition in aform suitable for parenteral administration comprising a solution ofE-(3)- 2-(phenylcarbamoyl)ethenyl!-4,6-dichloroindole-2-carboxylic acidor a physiologically acceptable salt thereof, in an isotonic sugarsolution containing a water miscible organic solvent for the compound,said composition having a pH within the range 7 to 9.

The isotonic sugar solution for use in the composition is convenientlyan aqueous dextrose solution such as 2 to 5% dextrose solution. Examplesof suitable alternative isotonic sugar solutions include thosecontaining mannitol or sorbitol.

Conveniently, the composition according to the invention is preparedfrom the glycine antagonist E-3- 2-(phenylcarbamoyl)etheny!-4,6-dichloroindole-2-carboxylic acid in the form of the freeacid or more particularly in the form of the sodium salt thereof.

The amount of the glycine antagonist (expressed in terms of the freeacid) in the formulation is preferably within the range 0.1 to 80 mg/ml.

If necessary, the pH of the solution may be adjusted by the addition ofa suitable base such as aqueous sodium hydroxide. More convenientlyhowever the pH of the solution may be adjusted to and/or maintainedwithin the range 7 to 9 e.g 8.0 to 9.0 by the use of a suitable buffersalt. Examples of suitable buffer salts includetris(hydroxymethyl)aminomethane or alkali metal salts of citric acid andor phosphoric add e.g. disodium phosphate. A particularly convenientbuffer salt for use in the invention is tris(hydroxymethyl)aminomethane.

Suitable water miscible organic solvents for use in the formulationinclude propylene glycol, glycofurol, ethanol, benzyl alcohol, glycerol,polyethylene glycols, N-methyl pyrrolidone or dimethylacetamide. Theamount of water miscible organic solvent present is conveniently withinthe range of 0.1 to 40% by weight of the total formulation.

The formulation according to the invention may be administered in theform of a bolus injection or intravenous infusion. For the bolusinjection the amount of water miscible organic solvent present isconveniently within the range 5 to 40% and the concentration of theglycine antagonist is conveniently within the range of 10 to 80 mg/mle.g. 20-70 mg/ml. A particularly convenient water miscible organicsolvent for use in the bolus injection is glycofurol. The isotonic sugarsolution for use in the bolus injection is conveniently an aqueousmannitol solution.

For the intravenous infusion the amount of water miscible organicsolvent is conveniently within the range 1 to 4% and the concentrationof the glycine antagonist is conveniently in the range of 0.1 to 5 mg/mle.g. 0.5 to 2 mg/ml. A particularly convenient water miscible organicsolvent for use in intravenous infusion is propylene glycol. Aparticularly useful sugar for use in the intravenous infusionformulation is dextrose.

For the intravenous infusion formulation and more particularly thosewherein the concentration of glycine antagonists (expressed as the freeacid) is higher than 0.8 mg/ml the solubility of the glycine antagonistin the infusion solution may be improved or enhanced by the addition ofethylene diamine tetraacetic add (EDTA) and/or physiologicallyacceptable salts thereof. Examples of suitable salts of EDTA includeammonium salts such as the diammonium salt or alkali metal salts as suchthe di, tri or tetra sodium or potassium salts thereof. A particularlyconvenient salt is the disodium salt e.g. EDTA disodium salt dihydrate.The minimum amount of EDTA or a salt thereof required to ensure goodsolubility will depend upon a number of factors including the choice ofwater miscible organic solvent and or the sugar present, however actualminimum amount required for a given formulation may be readilydetermined by simple experimentation. As a general rule however theminimum amount of EDTA or a salt thereof required (expressed as freeadd) will be in the region of 0.3% of the amount of glycine antagonist(expressed as a free acid) present. It will be appreciated that theamount of EDTA or a salt thereof present in the formulation may be morethan the minimum required to achieve the desired level of solubility ofthe glycine antagonist in the formulation.

The composition according to the invention and more particularly thecomposition for administration as a bolus injection may also contain asurfactant. Examples of suitable surfactants include polysorbates e.g.polysorbate 80.

Conveniently, the formulation according to the invention may be preparedby dissolving the glycine antagonist in the water miscible organicsolvent or an aqueous mixture thereof. Also if required the buffer saltand or the EDTA or a salt thereof may be added at this time. Whendesired the resultant solution is then mixed with the isotonic sugarsolution.

The following examples illustrate the invention. In these examples theglycine antagonist is used in the form of its sodium salt.

INFUSION FORMULATION EAMPLE A

    ______________________________________                         Amount per ml    ______________________________________    Glycine antagonist     1.69    mg    Tris(hydroxymethyl)aminomethane                           0.72    mg    EDTA disodium salt dihydrate                           0.00768 mg    Water                  3.192   mg    Propylene glycol       0.0194  ml    Dextrose solution 5% w/v                           qs to 1 ml    ______________________________________

The tris(hydroxymedthyl)aminomethane and the EDTA disodium saltdihydrate were dissolved in water, the propylene glycol was added andthe glycine antagonist was dissolved therein. The solution was filteredthrough a sterile 0.2 micron sterilising filter and filled in acontainer that was finally sterilised by autoclaving.

The solution was then diluted with the 5% dextrose solution suitable forinjection.

EXAMPLE B

    ______________________________________                         Amount per ml    ______________________________________    Glycine antagonist     0.83    mg    Tris(hydroxymethyl)aminomethane                           0.36    Water                  1.596    Propylene glycol       0.0097  ml    Dextrose solution 5%   qs to 1 ml    ______________________________________

Example B was prepared using the same procedure as described for exampleA except that the EDTA disodium salt dihydrate was omitted.

EXAMPLE C

    ______________________________________                        Amount per ml    ______________________________________    Glycine antagonist    0.83    Disodium phosphate    0.7     mg    Propylene glycol      0.016   ml    Dextrose solution 5% w/v                          qs to 1 ml    ______________________________________

The glycine antagonist was dissolved in the propylene glycol, thesolution filtered through a sterile 0.2 micron sterilising filter. Thesolution was then mixed with the 5% dextrose solution suitable forinjection containing the disodium phosphate. Conveniently the mixing maybe carried out in a container for infusion.

BOLUS INJECTION

    ______________________________________                         Amount per ml    ______________________________________    Glycine antagonist     70.6    mg    Polysorbate 80         10      mg    Tris(hydroxymethyl)aminomethane                           1.3     mg    Glycofurol             300     mg    5% Aqueous Mannitol    qs to 1 ml    ______________________________________

A solution of tris(hydroxymethyl)aminomethane in the 5% aqueous mannitolis added portionwise to a solution of the gylcine antagonist in amixture of the polysorbate 80 and glycofurol. The resulting solution isfiltered through a sterile 0.2 micron sterilising filter, filled intocontainers and then sterilised by autoclaving.

We claim:
 1. A pharmaceutical composition in a form suitable forparenteral administration comprising a solution of a glycine antagonistwhich is (E)-3-2-(phenylcarbamoyl)ethenyl!-4,6-dichloroindole-2-carboxylic acid or aphysiologically acceptable salt thereof, in an isotonic sugar solutioncontaining a water miscible organic solvent for the compound, saidformulation having a pH within the range of 7 to
 9. 2. A pharmaceuticalcomposition as claimed in claim 1 having a pH in the range 8.0 to 9.0.3. A pharmaceutical composition as claimed in claim 1 wherein pH isadjusted or maintained by means of a suitable buffer salt.
 4. Apharmaceutical composition as claimed in claim 3 wherein the buffer saltis (tris hydroxymethyl)aminomethane.
 5. A pharmaceutical composition asclaimed in claim 1 in a form suitable for intravenous infusion.
 6. Apharmaceutical composition as claimed in claim 5 containing ethylenediamine tetra acetic acid and or a physiologically acceptable saltsthereof.
 7. A pharmaceutical composition as claimed in claim 5 whereinthe concentration of the glycine antagonist, expressed in terms of thefree acid, is within the range 0.5 to 2 mg/ml.
 8. A pharmaceuticalcomposition as claimed in claim 5 wherein the water miscible organicsolvent is propylene glycol.
 9. A pharmaceutical composition as claimedin claim 5 wherein the isotonic sugar solution is an aqueous dextrosesolution.
 10. A pharmaceutical composition as claimed in claim 1 in aform suitable for administration as a bolus injection.
 11. Apharmaceutical composition as claimed in claim 10 wherein theconcentration of the glycine antagonist, expressed in terms of the freeacid, is within the range 10 to 80 mg/ml.
 12. A pharmaceuticalcomposition as claimed in claim 10 wherein the water miscible organicsolvent is glycofurol.
 13. A pharmaceutical composition as claimed inclaim 10 wherein the sugar solution is aqueous mannitol.
 14. Apharmaceutical composition as claimed in claim 10 containing asurfactant.
 15. A pharmaceutical composition as claimed claim 1 whereinthe composition is prepared using the sodium salt of (E)-3-2-(phenylcarbamoyl)ethenyl!4,6-dichloroindole 2-carboxylic acid.